Beyond knockout A novel homodimerization-targeting MyD88 inhibitor prevents and cures type 1 diabetes in NOD mice
Beyond knockout A novel homodimerization-targeting MyD88 inhibitor prevents and cures type 1 diabetes in NOD mice
复制标题
超越敲除 一种新型同二聚化靶向 MyD88 抑制剂可预防和治愈 NOD 小鼠的 1 型糖尿病
DOI：
10.1016/j.metabol.2016.05.005
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发表时间：
2016
影响因子：
9.8
通讯作者：
Zhou Ping
中科院分区：
文献类型：
--
作者：
Zhang Xue;Xing Shuai;Li Mingqiang;Zhang Limin;Xie Lin;He Wentao;Liu Jianhua;Chang Sheng;Jiang Fengchao;Zhou Ping
髓样分化因子88（MyD 88）在1型糖尿病（T1 D）的发生发展中起重要作用。本研究旨在探讨自制MyD 88抑制剂TJ-M2010 -6对T1 D的预防和治疗作用。方法采用分子对接和免疫共沉淀技术，研究TJ-M2010 -6对MyD 88同源二聚化的抑制作用。结果TJ-M2010 - 6与MyD 88 TIR结构域的氨基酸残基相互作用，抑制MyD 88同源二聚化。连续给药TJ-M2010-6可显著降低NOD小鼠在观察期内的糖尿病发病率（36. 4% vs. 80%，P < 0.01）。虽然立即TJ-M2010-6治疗组显示出血糖水平上升的延迟，但延迟治疗组没有显示出这种效果。机制研究表明，TJ-M2010-6治疗显著抑制体内胰岛炎。TJ-M2010-6在体外可抑制DCs的成熟，从而抑制T细胞活化和炎性细胞因子的分泌。结论MyD 88抑制剂靶向天然免疫系统的策略对T1 D的防治具有重要意义。
Introduction and aimsStudies have reported that myeloid differentiation factor 88 (MyD88) plays an important role in the development of type 1 diabetes (T1D). The aim of this study was to determine the effects of the self-created MyD88 inhibitor, TJ-M2010-6, in preventing and treating T1D.MethodsMolecule docking and co-immunoprecipitation were used to determine the suppressing capability of TJ-M2010-6 on the homodimerization of MyD88. The preventive and therapeutic effects of TJ-M2010-6 were tested in NOD mice.ResultsTJ-M2010-6 interacted with amino acid residues of the MyD88 TIR domain and inhibited MyD88 homodimerization. Continuous administration of TJ-M2010-6 significantly reduced the onset of diabetes during the observation period in NOD mice (36.4% vs. 80%,P< 0.01). Although the immediate TJ-M2010-6 treatment group showed a retardation in the rise of their blood glucose level, the delayed treatment group did not show this effect. Mechanism studies have shown that TJ-M2010-6 treatment significantly inhibits insulitis in vivo. In vitro, TJ-M2010-6 inhibited the maturation of DCs, leading to the suppression of T cell activation and inflammatory cytokine secretion.ConclusionsThese results demonstrated that the strategy targeted at the innate immune system using the MyD88 inhibitor had a profound significance in preventing and treating T1D.